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Role of gut-liver axis and glucagon-like peptide-1 receptor agonists in the treatment of metabolic dysfunction-associated fatty liver disease

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World Journal of Gastroenterology 2024年第23期30卷 2964-2980页

作者： Jakub Rochoń Piotr Kalinowski Ksenia Szymanek-Majchrzak MichałGrąt Department of General Transplant and Liver SurgeryMedical University of WarsawWarsaw 02-097Poland Department of Medical Microbiology Medical University of WarsawWarsaw 02-004Poland

Metabolic dysfunction-associated fatty liver disease(MAFLD)is a hepatic manifestation of the metabolic syndrome.It is one of the most common liver diseases worldwide and shows increasing prevalence rates in most countries.MAFLD is a progressive disease with the most severe cases presenting as advanced fibrosis or cirrhosis with an increased risk of hepatocellular carcinoma.Gut microbiota play a significant role in the pathogenesis and progression of MAFLD by disrupting the gut-liver axis.The mechanisms involved in maintaining gut-liver axis homeostasis are complex.One critical aspect involves preserving an appropriate intestinal barrier permeability and levels of intestinal lumen metabolites to ensure gutliver axis functionality.An increase in intestinal barrier permeability induces metabolic endotoxemia that leads to steatohepatitis.Moreover,alterations in the absorption of various metabolites can affect liver metabolism and induce liver steatosis and fibrosis.glucagon-like peptide-1 receptor agonists(GLP-1 RAs)are a class of drugs developed for the treatment of type 2 diabetes mellitus.They are also commonly used to combat obesity and have been proven to be effective in reversing hepatic steatosis.The mechanisms reported to be involved in this effect include an improved regulation of glycemia,reduced lipid synthesis,β-oxidation of free fatty acids,and induction of autophagy in hepatic cells.Recently,multiple peptide receptor agonists have been introduced and are expected to increase the effectiveness of the treatment.A modulation of gut microbiota has also been observed with the use of these drugs that may contribute to the amelioration of MAFLD.This review presents the current understanding of the role of the gutliver axis in the development of MAFLD and use of members of the GLP-1 RA family as pleiotropic agents in the treatment of MAFLD.

关键词： Metabolic dysfunction-associated fatty liver disease Metabolic dysfunction-associated steatohepatitis Nonalcoholic fatty liver disease Non-alcoholic steatohepatitis Metabolic syndrome Obesity Gastrointestinal microbiota glucagon-like peptide-1 glucagon-like peptide-2 Bariatric surgery

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The prolonged effect of glucagon-like peptide 2 pretreatment on growth performance and intestinal development of weaned piglets

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Journal of Animal Science and Biotechnology 2016年第4期7卷 579-587页

作者： Qiuhong Deng Gang Jia Hua Zhao Zheng li Chen Xiao ling Chen Guang mang Liu Kang ning Wang Animal Nutrition Institute Sichuan Agricultural University College of Animal Medicine Sichuan Agricultural University

Background： glucagon-like peptide 2 （GLP-2） is a potent epithelium-specific intestinal growth factor. The aim of this study was to demonstrate the prolonged effect of GLP-2 on the growth performance of weaned piglets. Forty piglets weaned at the age of 28 d with an average BW of 6.8 ＋ 0.4 kg were assigned to four treatments：（i） non- challenged control; （ii） LPS-challenged control; （iii） LPS ＋ low GLP-2; and （iv） LPS ＋ high GLP-2. Piglets in groups （i）, （ii）, and （iv） were s.c. injected with PBS supplemented with human [Gly2]GLP-21-34 at doses of 0, 2 and 10 nmol/kg BW per day for seven consecutive days. BW, gain：feed ratio （G：F）, and plasma GLP-2 levels were determined on d 0 7, and 14 after weaning. Piglets were challenged with i.p. administration of Escherichia coil lipopolysaccharide （LPS） at a dose of 100 pg/kg on d 14 to induce intestinal damage. Twenty-four hours later, intestinal tract samples were collected to assess intestinal morphology and quantify enzyme activity. Results： Plasma GLP-2 levels decreased after weaning, but in the high GLP-2 group, plasma GLP-2 was maintained on d 7 and even increased to a level higher than the preweaning level on d ]4 （P 〈 0.05）. High GLP-2 treatment significantly increased the duodenal, jejunal and ileal weight, as well as the gross weight of the small intestine （SI）, and the SI weight index （P 〈 0.05）. LPS caused villous atrophy and disrupted intestinal morphology in the duodenum, jejunum and ileum. GLP-2 also significantly increased the villus height and the villus height/crypt depth ratio （VCR） of the duodenum, jejunum, and ileum （P 〈 0.05）. Histological examination revealed that in GLP-2-treated groups, the integrity of the villus was maintained, and the villus was protected against LPS-induced damage. GLP-2 significantly increased the activity of alkaline phosphatase （AKP）, y-glutamyltranspeptidase （y-G-i-）, and pancreatic lipase in the duodenum and jejunum （P 〈 0.05）. GLP-2 treatment also significantly increased the average daily gain （ADG） and G：F of piglets at

关键词： Escherichia coil lipopolysaccharide glucagon-like peptide-2 Growth performance Intestinal enzymes Smallintestinal morphology Weaned piglets

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glucagon-like peptide-2 exhibits protective effect on hepatic ischemia-reperfusion injury in rats

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Frontiers of Medicine 2015年第3期9卷 368-373页

作者： Naci Topaloglu Adem Kucuk Sule Yildirm Mustafa Tekin Havva Erdem Mustafa Deniz Canakkale Onsekiz Mart University Medical Faculty Department of Pediatrics Canakkale Turkey Diizce Atatiirk State Hospital Department of Pediatric Surgery Diizce Turkey Diizce University Medical Faculty Department of Pathology Diizce Turkey Canakkale Onsekiz Mart University Medical Faculty Department of Physiology Canakkale Turkey

glucagon-like peptide-2 （GLP-2） has potent anti-inflammatory effects and protects against experimental ischemia/reperfusion （I/R） injury in pulmonary, intestinal, and myocardial tissue. However, its protective abilities against I/R injury in the liver are unknown. We investigated the potential role of GLP-2 pretreatment on hepatic I/R injury in rats. A total of 24 rats were randomly divided into three groups （n = 8）. The first group was the control group; the second group was the vehicle-treated hepatic ischemia/reperfusion （HIR, vehicle saline-treated） group; and the third group was the GLP-2 pretreated I/R （GLP2-IR） group. Each rat in the third group was intraperitoneally administered 5 ~tg GLP-2 for 5 d before the procedure. A portal triad was created to induce ischemia with a vascular atraumatic clamp. After 40 min, the clamp was released to initiate hepatic reperfusion for 6 h. Blood samples and tissue specimens from the fiver were obtained. Alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels significantly increased in the saline- treated HIR group （P 〈 0.001）, whereas GLP-2 pretreatment significantly decreased their levels （P 〈 0.01）. Our data suggested that GLP-2 pretreatment may have a protective effect on liver I/R injury. However, dose-response studies are necessary to determine the most effective dose.

关键词： ischemia/reperfusion liver glucagon-like peptide-2 alanine aminotransferase

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glucagon-like peptide-2 modulates the nitrergic neurotransmission in strips from the mouse gastric fundus

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World Journal of Gastroenterology 2017年第40期23卷 7211-7220页

作者： Rachele Garella Eglantina Idrizaj Chiara Traini Roberta Squecco Maria Giuliana Vannucchi Maria Caterina Baccari Department of Experimental and Clinical Medicine Section of Physiology University of Florence Department of Experimental and Clinical Medicine Histology and Embryology Research Unit University of Florence

AIM To investigate whether glucagon-like peptide-2(GLP-2) influences the neurally-induced responses in gastric strips from mice, since no data are available. METHODS For functional experiments, gastric fundal strips were mounted in organ baths containing Krebs-Henseleit solution. Mechanical responses were recorded via forcedisplacement transducers, which were coupled to a polygraph for continuous recording of isometric tension. Electrical field stimulation(EFS) was applied via two platinum wire rings through which the preparationwas threaded. The effects of GLP-2(2 and 20 nmol/L) were evaluated on the neurally-induced contractile and relaxant responses elicited by EFS. Neuronal nitric oxide synthase(n NOS) enzyme was evaluated by immunohistochemistry.RESULTS In the functional experiments, electrical field stimulation(EFS, 4-16 Hz) induced tetrodotoxin(TTX)-sensitive contractile responses, which were reduced in amplitude by GLP-2(P 2 no longer influenced the neurally-evoked contractile responses(P > 0.05). The direct smooth muscle response to methacholine was not influenced by GLP-2(P > 0.05). In the presence of guanethidine and carbachol, the addition of GLP-2 to the bath medium evoked TTX-sensitive relaxant responses that were unaffected by L-NNA(P > 0.05). EFS induced a fast NO-mediated relaxation, whose amplitude was enhanced in the presence of the hormone(P 2 exposure. CONCLUSION The results demonstrate that in gastric fundal strips, GLP-2 influences the amplitude of neurally-induced responses through the modulation of the nitrergic neurotransmission and increases n NOS expression.

关键词： Immunohistochemistry Gastric motility glucagon-like peptide-2 Neuronal nitric oxide synthase Non-adrenergic non-cholinergic neurotransmission

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